Title

Authors

Date of Completion

January 2004

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

Lymphatic Filariasis is a tropical disease caused by large tissue dwelling nematode parasites, Wuchereria bancrofti, Brugia malayi and Brugia timori. Mammalian immune responses involved in host protection from such infections are poorly understood. Utilizing a murine intraperitoneal Brugia infection model, previous reports from our lab have suggested that formation of ‘granuloma’ around the larvae to be the predominant mechanism involved in worm elimination. Granuloma formation is likely dependent on influx of cells into the site of infection followed by adherence of the cells to the larvae. Detailed analysis of the cellular responses in the peritoneal cavity following Brugia infection, suggest that T cells are critical in recruitment of cells to the site of infection, especially eosinophils, and in activation of macrophages. We evaluate the importance of eosinophils in host protection by using genetic and pharmacological ablation of IL-5. Studies from IL-5−/− mice illustrate that while IL-5 dependent mechanisms are critical in primary infections, they are dispensable during challenge infections. In addition to deficiency in eosinophil numbers, IL-5−/− mice manifest a significant defect in serum IgM levels. Moreover, only serum IgM levels correlated with worm recoveries observed in IL-5−/− mice. Abrogation of eosinophilia by monoclonal antibody to IL-5 or CCR3 suggests a significant role for eosinophils in worm elimination. However, worm elimination was not impaired in mice lacking eosinophil specific granule proteins Eosinophil Peroxidase (EPO) and Major Basic Protein (MBP). Finally, the role of IgM in granuloma formation was studied in vitro. Surprisingly, IgM appears to be both necessary and sufficient to mediate cell adherence to Brugia L3. This phenomenon seems to be complement independent and facilitated by direct interactions between IgM, peritoneal cells and the larvae. These results demonstrate for the first time that IgM, like IgG and IgE, can mediate an ADCC like response against large pathogens. The potential involvement of the recently discovered Fcα/μ receptor and the polymeric immunoglobulin receptor (pIgR) in mediating such responses are discussed. ^